Streptococcal cell wall arthritis in LEW/N rats closely resembles rheumatoid arthritis in humans. In addition to other growth factors, recent data have implicated heparin binding growth factor (HBGF-1) in the disease process. We have previously presented data indicating that a defective hypothalamic-pituitary-adrenal (HPA) axis response is associated with the extreme susceptibility to arthritis in LEW/N rats. During the past year, we have extended our studies of neuroendocrine regulatory mechanisms. In addition to the profound defect in responsiveness to IL-1 and streptococcal cell walls, LEW/N rats, in marked contrast to arthritis-resistant F344/N rats, are deficient in their responses to a variety of neurotransmitters as well. Receptor affinities and concentrations were the similar. A data considered, our current results suggest that the defect in arthritis-prone LEW/N involves a defect in the mechanisms that transduce the activation of the gene encoding corticotropin releasing hormone or CRH. These observations provide new insights into the role of the stress response and the development of human autoimmune diseases.